A substantial amount of information linking the hepatitis B virus and hepatocellular carcinoma has been generated along epidemiological and serological lines. The objectives of the research proposed here are to obtain data to more strongly link the virus in the direct production of hepatocellular carcinoma. Using the techniques of in vitro and in situ nucleic acid hybridization, homologous DNA will be sought to the hepatitis B Dane particle DNA in hepatitis B associated and nonassociated chronic liver disease and malignancy. Attempts will be made to directly localize the homologous DNA to the cell genome by 1) in situ hybridization to metaphase chromosomal spreads from human hepatocellular carcinoma tissue culture line and 2) further evaluation of high molecular weight DNA from chronically infected liver which is hybridizable to viral DNA probe. In addition, to further understand the events leading from acute infection to chronic infection to malignant transformation, a newly described animal model involving Marmota monax, the common woodchuck, will be investigated for its applicability to the hepatitis B setting. Also, human hepatoma tissue cell lines will be transplanted into nude athymic mice to further observe anti-viral, anti-tumor and immunologic manipulation of the malignant cells.